The present stereoisomers are structurally related to some sympathomimetic drugs. Generally, sympathomimetic amines act by binding to α- and β-adrenergic receptors. Such receptor binding can result in vascular constriction, reduced blood flow and/or reduced secretion of fluids into the surrounding tissues, which can decrease the amount of mucous secreted into nasal passages. Sympathomimetic drugs are thus used to treat nasal congestion, allergies and colds. In addition, sympathomimetic amines may affect the cardiovascular, urinary, central nervous and endocrine systems. Johnson et al., 13 Pharmacotherapy 1105 (1993). Sympathomimetic drugs can influence the smooth muscles and the activity of the central nervous system. Thus, sympathomimetic amines are also used as bronchodilators, appetite suppressants and mydriatic agents.
According to the present invention, stereoisomers with particular structural configurations interact more selectively with the receptors involved in sympathomimetic action than do other types of stereoisomers. Compounds with more than one chiral center that differ in the configuration of some but not all of the chiral centers are called diastereomers. Compounds that have the same composition but are mirror images of each other are called enantiomers. A chiral center is an asymmetric carbon atom which can exist in two different, mirror-image configurations. Compounds with such chiral centers have the ability to rotate the plane of plane-polarized light. The prefixes d and l, or (+) and (−) identify the direction in which a stereoisomer rotates light. The d or (+)-stereoisomer is dextrorotatory. In contrast, the l or (−)-stereoisomer is levorotatory. A mixture of (+) and (−)-enantiomers is called a racemic mixture.
An alternative classification system for stereoisomers exists where prefixes (S) and (R) are used, based on the structural configuration of the chiral center, rather than on the optical activity of the compound.
For example, (+)-pseudoephedrine is known to be a sympathomimetic amine which binds to α-adrenergic receptors. The structures of (+)-pseudoephedrine and (−)-pseudoephedrine are provided below.
(+)-Pseudoephedrine is a known decongestant sold under the tradename Sudafed®. However, (+)-pseudoephedrine has undesirable side effects, including central nervous system stimulation, lightheadedness, nervousness, anxiety, paranoia, heart arrhythmia, atrial fibrillations and premature ventricular contractions. 95 AMERICAN HOSPITAL FORMULATORY SERVICE 847–48. Moreover, (+)-pseudoephedrine unfortunately can be converted into the psychoactive drug, methamphetamine, by simply converting the hydroxyl, which is in the S-configuration, to the hydrogen found in methamphetamine. Hence, a need exists for a molecule which binds to an adrenergic receptor, has the beneficial decongestant activities of (+)-pseudoephedrine, and which reduces not only its adverse side effects, but its methamphetamine-conversion problem.
(−)-Ephedrine and the racemic mixture of (−)- and (+)-ephedrine also bind adrenergic receptors and have been used for bronchodilation. (−)-Ephedrine and the racemic mixture of (−) and (+)-ephedrine relax smooth muscle, stimulate metabolism, stimulate the central nervous system, but can have significant cardiovascular effects. 95 AMERICAN HOSPITAL FORMULATORY SERVICE 815. Accordingly, a need exists for molecules which bind adrenergic receptors, without the undesirable side effects of (−)-ephedrine and the racemic mixture of (−)-ephedrine and (+)-ephedrine.
Similarly, the racemic mixture of (+)- and (−)-phenylpropanolamine, is known to bind adrenergic receptors, and has been used as a decongestant or an anoretic. However, the racemic mixture has undesirable side effects—it may be contraindicated in patients having glaucoma and is known to stimulate the central nervous system. 95 AMERICAN HOSPITAL FORMULATORY SERVICE 846. Hence, a need exists for a composition having the beneficial activities of (+)- and (−)-phenylpropanolamine, without their undesirable side effects.